With
one percent of the world's population suffering from schizophrenia, there
is a rush among researchers to identify the inherited component of this
complex and still mysterious disease. Despite many promising studies,
no schizophrenia susceptibility genes have been found. Now, a group of
American scientists and their Danish collaborators are taking a different
approach. Although still probing the human genome, the team is studying
viruses that first invaded our lives millions of years ago and are still
causing trouble.

"As the first study of its kind, this investigation could be very important,"
says Robert Yolken, who heads the Stanley Division of Neurovirology at
Johns Hopkins Medical School, in Baltimore. Yolken believes that schizophrenia
may be linked to so-called endogenous retroviruses.

These poorly understood bugs are intriguing. Unlike all other viruses,
they do not infect their host; rather, they are inherited as part of the
human genomeeach of us has several classes of viral DNA sequences
in every cell. The sequences may have multiplied and become a part of
our genetic heritage after hitching a ride on the primate genome millions
of years ago. Today, the viral sequences comprise about half of one percent
of all human DNA.

The hypothesis: Infections during
pregnancy activate dormant viruses, disrupting brain development and
increasing the risk for schizophrenia later in life.

Normally, the viral sequences are harmless and lie dormantmost
are relics that cannot be transcribed into proteins. But some are still
intact and can be activated by various agents, such as infection by viruses
or microbes. "We hypothesize that in schizophrenia endogenous retroviruses
are activated by infections occurring during pregnancy," explains Yolken.
"Activation leads to disturbances of fetal brain development, which pave
the way for development of schizophrenia later in life."

Though Yolken's idea is still a theory, it has some support. Many studies
have identified morphological changes in schizophrenic brains, ranging
from enlarged ventricles to altered cell structures and protein levels
in certain brain regions. There is evidence that infection during pregnancy
plays a role in schizophrenia. A study begun in the 1960s involving 60,000
pregnant women found that children born to mothers infected with herpes
virus are five times more likely than other children to develop schizophrenia.

"We have found antibodies to retroviral protein in these women, suggesting
that endogenous activation has occurred," says Yolken. Furthermore, Håkon
Karlsson, a member of Yolken's group, recently identified traces of active
retrovirus in spinal fluid from a group of schizophrenics suffering their
first episode of the illness. No such traces showed up in controls.

To test the connection between retroviruses, early infection and schizophrenia,
the Johns Hopkins group teamed up with colleagues in Denmark. The Danish
researchers bring unique resources to the study.

Clinical biochemist Bent Nørgaard Pedersen, of Statens Serum Institute,
in Copenhagen, has a collection of blood samples taken from all Danish
newborns since 1981 as part of the routine screening for metabolic disorders.
Psychiatric epidemiologist Preben Bo Mortensen, of Århus University, offers
access to Denmark's centralized psychiatric registry. The database contains
information on every patient who came into contact with the country's
psychiatric health care system since the sixties.

Much about schizophrenia is determined
in and around pregnancy

"In the registry, we have identified 600 schizophrenic patients age 14-15,"
says Pedersen. "By using the personal identification number (carried by
every Dane), we have pulled out these patients' infant blood samples."
Together with 1,200 age-matched controls, these anonymous samples are
on their way to Yolken's laboratory in Baltimore. His team will look for
traces of active retrovirus and infections that were present around the
time of birth.

"We are especially interested in herpes, but we test for the standard
battery of viruses, including cytomegalovirus, toxoplasma and rubella,"
says Yolken. The results will be sent back to Mortensen, whose analyses
are expected to reveal possible links between infection and schizophrenia.

"Epidemiological investigations in various populations have shown us
that schizophrenia is a complex disorder," says Mortensen. Both a genetic
susceptibility and a considerable contribution from the environment are
required for the development of the disease, and Mortensen's mining of
the Danish registry has uncovered a host of environmental factors that
may be involved.

"It is now clear that much about schizophrenia is determined in and around
pregnancy," says Yolken. He points out that the cooperation between genes
and environment is exactly what makes the endogenous retrovirus theory
so appealing: "These viruses, which are also implicated in diseases such
as sclerosis and arthritis, make attractive candidates for the unknown
link that bridges the gap."

How this bridging happens is still largely unknown. Once activated, the
otherwise benign retroviruses seem to cause great damage in their genetic
neighborhood, perhaps by altering the expression of nearby genes. This
is where the individual's genetic susceptibility comes into play. "While
one person's genetic makeup is not affected by retro-viral activation,"
says Yolken, "the same activation may trigger a chain of events in another
individual."

Once schizophrenia susceptibility genes are identified, the genes can
be analyzed for the presence of endogenous viral sequences. Yolken is
particularly hopeful that the new study may raise the prospects for treatment
of schizophrenia. "If retroviral activation starts off processes leading
to the development of schizophrenia, it should be possible to treat or
even prevent the disease with anti-viral drugs," he says.

Herpes infection is common among schizophrenics, and many patients suffer
from intermittent worsening of the disease. Yolken is interested in testing
whether the standard herpes treatment can prevent such episodes. "There
is also the prospect of screening pregnant women for herpes infection
and treating the ones at risk," he says.